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Stroke-Like Episodes in PMM2-CDG: When the Lack of Other Evidence Is the Only Evidence

ABSTRACT: Phosphomannomutase 2 deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. PMM2-CDG patients develop chronic cerebellar atrophy as a neurological hallmark. However, other acute neurological phenomena such as stroke-like episodes (SLE), epilepsy, migraine, and cerebrovascular events, may also occur, and they are frequently the cause of disability and impaired quality of life. Among these, SLE are among the most stressful situations for families and doctors, as their risk factors are not known, their underlying pathomechanisms remain undiscovered, and clinical guidelines for diagnosis, prevention, and treatment are lacking. In this paper, the recent SLE experiences of two PMM2-CDG patients are examined to provide clinical clues to help improve diagnosis through a clinical constellation of symptoms and a clinical definition, but also to support a neuroelectrical hypothesis as an underlying mechanism. An up-to-date literature review will help to identify evidence-based and non-evidence-based management recommendations. Presently neuropediatricians and neurologists are not capable of diagnosing stroke-like episodes in an unequivocal way, so there is still a need to perform invasive studies (to rule out other acute diseases) that may, in the end, prove unnecessary or even harmful. However, reaching a correct and early diagnosis would lead not only to avoidance of invasive tests but also to better recognition, management, and understanding of the disease itself. There is a great need for understanding of SLE that may ultimately be very informative for the detection of patients at risk, and the future development of preventive and management measures.

SUBMITTER: Serrano M

PROVIDER: S-EPMC8542667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPhosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data.MethodsOur observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2-CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients' ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach's alpha. Spearman's rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ.ResultsICARS and ICARS subscores differed between patients and controls (p < 0.001). Interobserver agreement of ICARS was "almost perfect" (ICC = 0.99), with a "good" internal reliability (Cronbach's alpha = 0.72). ICARS was significantly correlated with the total NPCRS score (rs 0.90, p < 0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, inverse correlations between ICARS and midsagittal vermis relative diameter (rs -0.85, p = 0.003) and IQ (rs -0.94, p = 0.005) were found. Patients bearing p.E93A, p.C241S or p.R162W mutations presented a milder phenotype.ConclusionsICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite our limited sample size, the results show a good correlation between functional cerebellar assessment, IQ and neuroimaging. For the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated.

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Stroke-Like Episodes in PMM2-CDG: When the Lack of Other Evidence Is the Only Evidence

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